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Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy

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Treating statin-intolerant patients

This article was published in the following Dove Press journal: Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 27 April 2011 Number of times this article has been viewed

Marcello Arca Giovanni Pigna Atherosclerosis Unit, Department of Internal Medicine and Allied Medical Specialities, Sapienza University of Rome, Rome, Italy

Abstract: Statins are effective in reducing cardiovascular events and are safe for almost all patients. Nevertheless, intolerance to statins is frequently faced in clinical practice. This is mostly due to muscular symptoms (myalgia with or without increase of plasma creatinine kinase) and/or elevation of hepatic aminotransferases, which overall constitutes approximately two-thirds of reported adverse events during statin therapy. These side effects raise concerns in patients as well as in doctors and are likely to reduce patients’ adherence and, as a consequence, the cardiovascular benefit. Therefore, it is mandatory that clinicians improve their knowledge on the clinical aspects of muscular and hepatic side effects of statin therapy as well as their ability to manage patients with statin intolerance. Besides briefly examining the clinical aspects and the mechanisms that are proposed to be responsible for the most common statin-associated side effects, the main purpose of this article is to review the available approaches to manage statinintolerant patients. The first step is to determine whether the adverse events are indeed related to statin therapy. If so, lowering the dosage or changing statin, alternate dosing options, or the use of nonstatin compounds may be practical strategies. The cholesterol-lowering potency as well as the usefulness of these different approaches in treating statin-intolerant patients will be examined based on currently available data. However, the cardiovascular benefit of these strategies has not been well established, so their use has to be guided by a careful clinical assessment of each patient. Keywords: statin therapy, atorvastatin, rosuvastatin, aminotransferase levels, myopathy

Introduction

Correspondence: Marcello Arca Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Azienda Policlinico Umberto I,Viale del Policlinico, 155, 00161, Rome, Italy Tel +39 06 4451354 Fax +39 06 4463534 Email [email protected]

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Dovepress DOI: 10.2147/DMSO.S11244

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are the mainstay of lipid-lowering therapy because of their well-established efficacy for reducing cardiovascular disease (CVD) morbidity and mortality in various at-risk populations.1 In general, statin therapy is associated with rare occurrences of serious adverse events and is considered to be safe.2,3 Nevertheless, a significant proportion of subjects taking these drugs may experience some degree of intolerance. In particular, statin-induced myopathy (SIM) is by far the most common side effect. A less common side effect of statin therapy is the increase of serum aminotransferase levels, which is considered the manifestation of hepatic toxicity.4 Despite the fact that these adverse effects are reversed after treatment withdrawal, many patients with an indication for statins refuse therapy because of concerns about muscle or liver toxicity. This may represent a significant barrier to maximizing cardiovascular risk reduction for many patients with dyslipidemia. Therefore, a better understanding of the relatively common statin-related adverse effects may improve the

Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2011:4 155–166 155 © 2011 Arca and Pigna, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

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clinician’s ability to manage patients with these problems. In this review, after briefly recapitulating incidence data and mechanisms whereby statins may cause muscle-related or hepatic toxicity, we will examine management strategies for patients who are intolerant to statins due to these common adverse effects.

Clinical aspects and mechanisms of statin-associated adverse effects Several studies have evaluated the incidence of adverse events during statin therapy. In a meta-analysis of over 70,000 subjects in 18 primary and secondary prevention placebo-controlled trials, the number needed to harm (NNH) for any adverse event with statins was 197 versus 27, which was the number needed to treat (NNT) to prevent one cardiovascular event.5 In other words, treating 1,000 patients would prevent 37 cardiovascular events and cause 5 adverse events. In this analysis, serious adverse events, such as creatine kinase (CK) . 10 times upper limit of normal (ULN) or rhabdomyolysis, are rare and have a NNH of 3,400. Rhabdomyolysis alone was extremely rare with an NNH of 7,428. In the search for differences between statins, this study showed that fluvastatin, the least efficacious, had the lowest rate of adverse events, and atorvastatin, the most efficacious, had the highest rate. Simvastatin, pravastatin, lovastatin, and rosuvastatin appeared to have similar rates of adverse events. In a systematic review of 20 clinical trials, Law and Rudnicka6 reported that the incidence of myopathy and minor muscle pain incidence was 195 cases per 100,000 patient-years (95% confidence intervals [CI]: -38 to 410). The incidence of rhabdomyolysis was 1.6 cases per 100,000 patient-years (95% CI: -2.4 to 5.5). However, it must be noted that the frequency with which clinicians encounter SIM in real-world clinical practice is often much higher than that reported in clinical trials. One likely explanation for this discrepancy is that the rate of myopathy in clinical trials is artificially underestimated because patients at increased risk for statin-induced adverse effects tend to be excluded prior to randomization.7 Also, many patients in clinical practices may not be as healthy as those enrolled in clinical trials and often have more severe comorbidities. Data on the real-world incidence of SIM may be available through several drug side-effect reporting systems. For example, in the Food and Drug Administration’s (FDA) Adverse Event Reporting System database recorded until 2002, the reporting rates per million statin prescriptions was 0.38 cases for myopathy and 1.07 cases of rhabdomyolysis.8 However, this source might produce biased information due

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to the fact that the event reporting is voluntary and thus may have resulted in underreporting of adverse effects. To obtain data that are representative of the clinical practice, it may be helpful to examine databases from cohort studies or from closed systems such as managed care organizations. The Prediction of Muscular Risk in Observational Conditions (PRIMO) produced one of these databases.9 In the PRIMO study, over 7,900 hyperlipidemic patients treated with highdose statin therapy were enrolled in a 12-month, prospective observational follow-up. Muscle symptoms were reported by 11% of patients. This figure has been confirmed by others,10 so we can reasonably state that SIM may affect 10%–15% of statin users. The clinical presentation of statin myopathy varies from mild fatigue to rhabdomyolysis requiring hospitalization. The most frequently reported symptoms include myalgia, fatigue, weakness, generalized aching, and low back or proximal muscle pain.2,11,12 There have been less frequent complaints of tendon pain and nocturnal muscle cramps.11 According to well accepted definitions, myalgia is defined as muscular symptoms without CK elevations; myositis refers to muscle symptoms with CK elevation; and rhabdomyolysis is defined as muscle symptoms with marked CK elevations (.10 times ULN) with an elevated plasma creatinine and the occasional presence of brown urine.12 The temporal relationship between initiation of statin treatment and onset of symptoms is widely variable, as is the time between cessation of statin treatment and the resolution of symptoms. In a study that used two large UK primary care databases covering an active population of about 5 million people and including many patients with a follow-up period of over ten years, it has been reported that most SIM cases occur within the first 12 weeks of statin exposure, but few can be seen up to 52 weeks of treatment.13 SIM does not appear to be related to statin dosage. In a review of several atorvastatin trials, treatment-related myalgia occurred at a similar rate of 1.4% and 1.5% in subjects receiving 10 or 80 mg of atorvastatin compared with a rate of 0.7% with placebo.14 A retrospective analysis of safety from the PROVE-IT trial also suggested that statin adverse effects are not related to low density lipoprotein (LDL) level.15 In fact, muscular and hepatic side effects were found to occur at the same rate across all on-treatment LDL-cholesterol (LDL-C) levels, including very low levels of 40 mg/dL. This phenomenon has been confirmed in a recent meta-analysis comparing different statin doses and on-treatment LDL-C levels.16 Although the exact mechanisms causing SIM has not been determined, several hypotheses have been proposed. It has

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been suggested that cholesterol reduction with statins may perturb the integrity of the plasma membrane of myocytes because cholesterol plays a key role in cell membrane fluidity.17 Others have proposed that statins induce myopathy by favoring the deficiency of coenzyme Q10 (CoQ10), which is a metabolite of the HMG-CoA reductase pathway.18 CoQ10 plays a key role in the electron transport chain, and a reduction in this coenzyme could result in an abnormal mitochondrial respiratory function. However, several lines of evidence make these explanations unlikely. Firstly, when cholesterol is decreased by inhibiting squalene synthetase, no increase in myotoxicity is observed.19 Human and animal studies have demonstrated that statin treatment may reduce serum CoQ10 levels; however, myocyte CoQ10 levels have not been consistently decreased with statin treatment.20 Another possible explanation of SIM relates to the observation that statins induce the apoptosis or programmed cell death of myocytes by reducing isoprenoids levels. Isoprenoids are lipids produced by HMG-CoA reductase pathway. 21 Isoprenoids are linked to proteins by a process known as farnesylation. According to this theory, statins block the production of farnesyl pyrophosphate and this prevents the prenylation of GTP-binding proteins Ras, Rac, and Rho. A reduction in the levels of the prenylated forms of these proteins leads to increased cytosolic calcium levels with subsequent activation of the proteolytic enzymes capsase-3 and capsase-9, which have a central role in cell death. This theory is also supported by an in vitro study demonstrating that statin-induced apoptosis of muscle cells is prevented by supplementation with the isoprenoids farnesyl pyrophosphate and geranylgeranyl pyrophosphate but not CoQ10.22 Finally it has been proposed that statins impair intracellular calcium homeostasis by interfering with the mitochondrial respiratory chain and by affecting ryanodine receptor one (RyR1), which pumps calcium into the cytoplasm. Increased cytoplasmic calcium levels have been shown to cause cramps, myalgias, and apoptosis.23,24 Recently, genetic risk factors for statin myopathy have been identified. Investigators from the ongoing Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial hypothesized that strong associations might exist between treatment with a high-dose statin regimen and genetic variants that affect statin blood levels.25 In this trial, a genome-wide analysis demonstrated that myopathy was strongly associated with a single nucleotide polymorphism within intron 11 of SLCO1B1 on chromosome 12. SLCO1B1 is the gene that encodes the organic anion transporting polypeptide responsible for


Statin-intolerant patients

hepatic uptake of statins. In the SEARCH, 60% of the cases of myopathy were associated with SLCO1B1 variants. The most commonly encountered hepatic biochemical abnormality during statin therapy is the asymptomatic elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) which appears to be a class effect of statins.2,4 This has been also defined as ‘transaminitis’, in which liver enzymes are elevated in the absence of clear hepatoxicity. This condition is usually transient with full resolution following withdrawal of the drug, although this may take several months. It is rare for statins to cause isolated elevations in gamma-glutamyl transferase (GGT).26 Several reports indicate that the occurrence of aminotransferase elevation during statin therapy ranges from 1%–3%.27,28 This effect appears to be dose related29,30 and hence may be related to bioavailability. In a recent meta-analysis,16 it has been shown that atorvastatin 80 mg and simvastatin 80 mg are associated with a persistent elevation of ALT (.3 times ULN) up to 5 times compared to atoravastatin 10 mg and simvastatin 20–40 mg (0.2% vs 1.0%). Hepatocellular injury seen during statin therapy seems to be an early side effect as demonstrated in several statins trials where AST and ALT elevation appeared in the initial 3 months of treatment.31 Liver-related symptoms occurred on average 4 weeks (range 1 to 8 weeks) after initiation of treatment but resolved within 4 weeks of statin therapy discontinuation. The mechanism by which statins may induce hepatocellular injury is unclear. Animal studies have suggested that the depletion of mevalonate or one of its sterol metabolites caused by the inhibition of 3-hydroxyl, 3-methyl-glutaryl-CoA reductase (HMG-CoA) enzyme may be responsible for the elevated liver enzymes.32 It has been suggested that the inherent metabolic characteristics of statins may have some relevance. In fact, the different statins have distinctly different metabolic pathways, as simvastatin, lovastatin, fluvastatin, and atorvastatin are metabolized by cytochrome P450 system, whereas pravastatin, rosuvastatin, and pitavastatin undergo minimal hepatic metabolism. Moreover, statins vary in their degree of lipophilicity, which may have an impact on their likelihood of being associated with aminotransferase elevations. The meta-analysis by Dale et al33 demonstrated that the less lipophilic statins (pravastatin, rosuvastatin, atorvastatin, fluvastatin) increased the relative risk of aminotransferase elevation compared to the more lipophilic ones (lovastatin, simvastatin, cerivastatin). In this regard, it is interesting to note that the opposite has been observed for CK elevation.12,13 A clear explanation for this is not available even though one could implicate the hepatic organic


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anion transport protein (OATP or SLCO1B1) that plays an important role in facilitating the penetration of statin into the hepatocytes. It has been reported that genetic variations in SLCO1B1 have a larger effect on the area under the plasma concentration-time curve of atorvastatin than that observed with the more hydrophilic rosuvastatin.34 The natural history of elevated liver enzymes due to the long-term use of statins is poorly understood. However, it is recognized that in some individuals, this elevation is transient and may be physiological rather than pathological and that some patients display ‘adaptation’, where liver enzymes stabilize/normalize if the drug is not withdrawn.35 There are no studies that correlate hepatic histology with elevations in liver enzymes to differentiate between true hepatotoxicity and an adaptive process. The US National Lipid Association’s (NLA) Safety Assessment Task Force concluded in 2006 that there was no evidence of a relationship between elevated transaminases, statin therapy, and risk of significant liver injury.4 Furthermore, they also concluded that routine monitoring of liver enzymes did not identify those individuals at risk of developing idiosyncratic liver failure. In addition, recent evidence suggests that moderate elevation of transaminases should not contraindicate the initiation of statin therapy. A post-hoc analysis of the secondary prevention Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study,36 assessed the cardiovascular and liver outcomes in a total of 437 patients presenting moderately elevated liver enzymes (,3 times ULN) at enrollment, possibly associated with non-alcoholic fatty liver disease. Two hundred twentyseven of these individuals who were treated with a statin (mainly atorvastatin, 24 mg per day) had substantial improvement in liver tests (P , 0.0001), whereas the 210 individuals not treated with a statin had further increases of liver enzyme concentrations during the 3-year follow-up of this study. Furthermore, patients with abnormal liver tests who received a statin experienced fewer cardiovascular events in comparison to patients with abnormal liver tests who did not receive one (68% relative risk reduction, P , 0.0001). Interestingly, this cardiovascular benefit was greater (P = 0.0074) than it was in patients with normal liver enzymes. The most frequently seen histological appearance of statin-induced liver injury is inflammation of the portal tracts with mild piecemeal necrosis and focal periportal fibrosis.37 As serious hepatotoxicity caused by statins is rare, these findings are seldom seen. The FDA’s Adverse Event Reporting System database until 2004, reported a rate of 0.69 cases of liver failure/hepatitis per million statin prescriptions, a figure similar to that reported for liver failure/hepatitis in the general

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adult population.4 Analysis of an administrative database showed 6.1 to 12.8 hepatic events per 10,000 person-years of hospitalized patients on statins.38 None were hospitalized within 6 months of starting their statin. Furthermore, only 1 of the 51.741 patients who underwent liver transplantation between 1990 and 2002 was taking a marketed statin.27,39 However, recent literature indicates that potential remains for these more serious hepatotoxic reactions in association with statins. Adverse drug reaction reports from the UK Committee on Safety of Medicines show four deaths caused by atorvastatin-induced hepatotoxicity over an eight-year period (0.5 deaths per annum).40 In addition, there are also reports of rosuvastatin, fluvastatin, and atorvastatin inducing or revealing autoimmune disease, including autoimmune hepatitis. This is an extremely rare effect and there is evidence that the hepatic effect may be reversible when the drug is withdrawn.41–43 Finally, in very rare circumstances, statin therapy may cause liver failure.44 Overall, the long-term hepatic safety of statins is reassuring. It has been, in fact, reported that 24 million years of patient treatment with lovastatin reveal a rate of acute liver failure of 1 per 1.14 million patient-treatment years, which is similar to the rate of idiopathic acute liver failure.37 Nevertheless, the potential for statin-associated severe liver injury makes the monitoring of liver enzymes during this treatment important to recognize drug-induced liver injury as early as possible.

Strategies for managing statin intolerant patients The first step in the management of intolerance to statins is to rule out any possible conditions that increase the risk of developing SIM or aminotransferase elevations. A list of the most common of these conditions is reported in Table 1. The National Lipid Association Statin Safety Task Force has provided recommendations for the management of musclerelated symptoms in patients receiving statin therapy4 and these are incorporated in Figure 1. In summary, in patients with moderate symptoms and without significant CK elevation (, 5 × ULN), progress can be followed clinically. On the other hand, in patients with severe symptoms and in those with CK elevated more than 5 × ULN, statins should be stopped. Once CK is normalized, patients should be rechallenged with the same statin at the same dosage. Otherwise, different approaches can be considered (Table 2). The use of agents (coenzyme Q10 and vitamin D preparation) to alleviate muscular symptoms has also been proposed. Guidelines have also been issued to manage liver intolerance to statins,4,26,27 and these are summarized in Figure 2. Baseline


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Statin-intolerant patients

Table 1 Potential risk factors for statin-induced myopathy (SIM) and hepatic side effects of statins Statin-induced myopathy

Hepatic toxicity

Frailty and low body mass index Advanced age (.80 y) High physical activity Heavy alcohol consumption Drugs affecting statin metabolism (gemfibrozil, cyclosporin, amiodarone, macrolides antibiotics, verapamil, systemic use of azole antifungale, warfarin, protease inhibitors) Renal insufficiency Hypothyroidism Rheumatic diseases Metabolic muscle diseases Major surgery Genetic factors (CYP450 variants, drug transporter variants)

Acute viral diseases Alcohol-associated liver diseases Advanced chronic liver diseases Mildly lipophilic statins Genetic factors (CYP450 isoenzymes)

elevations of hepatic transaminases ,3 times ULN are not a contraindication to statin therapy. Many patients with diabetes, metabolic syndrome, or obesity have nonalcoholic fatty liver disease with transaminase levels fluctuating between 1.5 and 3 × ULN.29 After establishing that no other etiologies are responsible for the transaminase elevations, a statin at a Determine CK and rule out other causes of myopathy

Tolerable muscle pains but CK >5 × ULN

Tolerable muscle pains and no or mild CK elevation